The present invention relates to avermectin derivatives having antiparasitic activity.
Avermectins are antiparasitic antibiotics produced by Streptomyces avermitilis. Four main ingredients (Ala, A2a, B1a and B2a) have been known, and among them, avermectin B1a is known to have potent activity (Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 3-254678/1991).
Various derivatives have been synthesized so far to provide avermectin derivatives having higher activity. However, these derivatives fail to have fully satisfactory antiparasitic activity.
An object of the present invention is to provide avermectin derivatives having antiparasitic activity.
In order to find avermectin derivatives having higher antiparasitic activity, the inventors of the present invention synthesized various derivatives using avermectins B1a and B2a as starting materials. As a result, we succeeded in obtaining derivatives represented by the following general formula (I) which have high antiparasitic activity. The present invention was achieved on the basis of the findings.
The present invention thus provides compounds represented by the general formula (I) or salts thereof: 
wherein xe2x80x94X----Yxe2x80x94 represents xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94;
a line ---- between R1 and a carbon atom at the 4xe2x80x3-position represents a single or double bond;
a line ---- between R2 and a carbon atom at the 5-position represents a single or double bond;
1) when xe2x80x94X----Yxe2x80x94 represents xe2x80x94CHxe2x95x90CHxe2x80x94,
the line ---- between R1 and a carbon atom at the 4xe2x80x3-position represents a double bond;
R1 represents (R11)(R12)C [wherein R11 represents a substituted or unsubstituted lower alkyl group; a formyl group; a lower alkoxylcarbonyl group, the alkyl moiety of the said lower alkoxylcarbonyl group may be substituted with a heterocyclic group; xe2x80x94CHxe2x95x90Nxe2x80x94OR3 wherein R3 represents a hydrogen atom or a lower alkyl group; a lower alkenyloxycarbonyl group; xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94CONH2; a cyano group; xe2x80x94COR4 wherein R4 represents a hydroxyl group or N(R5)(R6) wherein R5 and R6 form a nitrogen containing heterocyclic group together with the adjacent nitrogen atom; a vinyl group substituted with a lower alkenyloxycarbonyl group; xe2x80x94COxe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94Rx wherein Rx represents a lower alkyl group; or xe2x80x94CHxe2x95x90CHxe2x80x94COOH; and R12 represents a hydrogen atom, or when R11 represents a cyano group, R12 represents a hydrogen atom or a lower alkyl group]; when the line ---- between R2 and a carbon atom at the 5-position represents a single bond, R2 represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group; or when the line ---- between R2 and a carbon atom at the 5-position represents a double bond, R2 forms a carbonyl group or a hydroxime group {xe2x80x94C(xe2x95x90NOH)}, together with the carbon atom at the 5-position;
2) when xe2x80x94X----Yxe2x80x94 represents xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94,
the line ---- between R1 and a carbon atom at the 4xe2x80x3-position represents a double bond;
R1 represents (R11a)(R12a)C [wherein R11a represents a lower alkoxycarbonyl group, the alkyl moiety of the said lower alkoxycarbonyl group may be substituted with a heterocyclic group, or xe2x80x94COOCH2CHxe2x95x90CH2; and R12a represents a hydrogen atom]; the line ---- between R2 and a carbon atom at the 5-position represents a single bond; and R2 represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group;
3) when xe2x80x94X----Yxe2x80x94 represents xe2x80x94CH2xe2x80x94CH2xe2x80x94,
R1 represents (R11b)(R12b)C [wherein R11b represents a cyano group, a carboxyl group, or a lower alkenyloxycarbonyl group; and R12b represents a hydrogen atom]; or when the line ---- between R1 and a carbon atom at the 4xe2x80x3-position represents a single bond, R1 may represent a carboxymethyl group or a cyanomethyl group; the line ---- between R2 and a carbon atom at the 5-position represents a single bond; and R2 represents a hydroxyl group, a lower alkoxyl group, or a tri(lower alkyl)silyloxy group;
4) when xe2x80x94X----Yxe2x80x94 represents xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94,
the line ---- between R1 and a carbon atom at the 4xe2x80x3-position represents a double bond;
R1 represents (R11c)(R12c)C [wherein R11c represents a cyano group, a carboxyl group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group; and R12c represents a hydrogen atom]; R13 represents a hydroxyl group or a lower alkylcabonyloxy group; the line ---- between R2 and a carbon atom at the 5-position represents a single bond; and R2 represents a hydroxyl group, a lower alkoxyl group or a tri(lower alkyl)silyloxy group.
Among the compounds of the general formula (I) according to the present invention, those wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94 or the salts thereof are preferred.
Among the compounds of the general formula (I) according to the present invention, those wherein xe2x80x94X----Yxe2x80x94 represents xe2x80x94CHxe2x95x90CHxe2x80x94, and R11 represents a substituted or unsubstituted lower alkyl group, a cyano group, or xe2x80x94COR4 wherein R4 has the same meaning as that defined above, or the salts thereof are also preferred.
Among the compounds of the general formula (I) according to the present invention, those wherein R2 is a hydroxyl group or a tri(lower alkyl)silyloxy group or the salts thereof are preferred.
Among the compounds of the general formula (I) according to the present invention, those wherein xe2x80x94X----Yxe2x80x94 represents xe2x80x94CH2xe2x80x94CH2xe2x80x94 or the salts thereof are preferred. Among them, those wherein R11b represents a cyano group or a carboxyl group or the salts thereof are preferred.
According to another aspect of the present invention, there are provided medicaments which comprise as an active ingredient the compound represented by the aforementioned general formula (I) or the physiologically acceptable salt thereof. The medicaments can be administered as antiparasitics to a mammal including a human.
According to further aspects of the present invention, there are provided a use of the compound represented by the aforementioned general formula (I) or the physiologically acceptable salt thereof for the manufacture of the aforementioned medicament; and a method for therapeutic treatment of parasitosis which comprises the step of administering a therapeutically effective amount of the compound represented by the aforementioned general formula (I) or the physiologically acceptable salt thereof to a mammal including a human.
Hereinafter the compounds represented by the general formula (I) are referred to as the compounds (I). The compounds of other formula numbers are abbreviated in a similar manner.
In the compounds (I) of the present invention, xe2x80x94X----Yxe2x80x94 represents xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94 (in each formula, the carbon atom on the left side corresponds to X.).
In the compounds (I) of the present invention, the compounds, wherein R2 is a hydroxyl group or a tri(lower alkyl)silyloxy group when xe2x80x94X----Yxe2x80x94 represents xe2x80x94CHxe2x95x90CHxe2x80x94 and the line ---- between R2 and a carbon atom at the 5-position represents a single bond, are referred to as the compounds (Ia), and those wherein xe2x80x94X----Yxe2x80x94 represents xe2x80x94CHxe2x95x90CHxe2x80x94 and R2 forms a carbonyl group or a hydroxime group together with the carbon atom at the 5-position are referred to as the compounds (Ic).
In the compounds (I) of the present invention, the compounds wherein xe2x80x94X----Yxe2x80x94 represents xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, the line ---- between R2 and a carbon atom at the 5-position represents a single bond, and R2 represents a hydroxyl group or a tri(lower alkyl)silyloxy group are referred to as the compounds (Ib).
In the compounds (I) of the present invention, the compounds wherein xe2x80x94X----Yxe2x80x94 represents xe2x80x94CH2xe2x80x94CH2xe2x80x94, the line ---- between R2 and a carbon atom at the 5-position represents a single bond, and R2 represents a hydroxyl group or a tri(lower alkyl)silyloxy group are sometimes referred to particularly as xe2x80x9civermectin derivatives.xe2x80x9d xe2x80x9cAvermectin derivativesxe2x80x9d referred to in the specification include the aforementioned ivermectin derivatives.
In the compounds (I) of the present invention, the compounds wherein xe2x80x94X----Yxe2x80x94 represents xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94 wherein R13 represents a hydroxyl group or a lower alkylcarbonyloxy group, the line ---- between R2 and a carbon atom at the 5-position represents a single bond, and R2 represents a hydroxyl group or a tri(lower alkyl)silyloxy group are sometimes referred to as the compounds (Id).
In the definition of each group in the compounds (I), the lower alkyl group may be any of C1-C8 linear, branched, and cyclic alkyl groups or a combination thereof, preferably a C1-C8 linear or branched alkyl group. The lower alkyl group includes, for example, a methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclopropylmethyl group, cyclobutyl group, pentyl group, hexyl group, heptyl group, octyl group, and the like. A lower alkyl moiety in functional groups having the lower alkyl moiety, such as the lower alkoxycarbonyl group, lower alkoxyl group, lower alkylcarbonyloxy group and tri(lower alkyl)silyloxy group has the same meaning as that defined in the aforementioned lower alkyl group unless otherwise specifically mentioned. The lower alkyl moieties in the tri(lower alkyl)silyloxy group may be the same or different.
Examples of a lower alkenyl moiety in the lower alkenyloxycarbonyl group include C2-C6 straight and branched alkenyl groups, for example, a vinyl group, allyl group, methacryl group, butenyl group, pentenyl group, hexenyl group, and the like. The number of double bonds present in the alkenyl group is not particularly limited, and preferably one.
The heterocyclic group may be either an aromatic or aliphatic heterocyclic group. Examples of the aromatic heterocyclic group include, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group which contains at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms. More specifically, examples include a pyridyl group, pyrrolyl group, furyl group, thienyl group, thiazolyl group, pyrazinyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, and oxazolyl group. Examples of the aliphatic heterocyclic group include, for example, a 5- or 6-membered monocyclic aliphatic heterocyclic group which contains at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms. More specifically, examples include a pyrrolidinyl group, tetrahydrofuryl group, and tetrahydropyranyl group.
The nitrogen containing heterocyclic group formed together with the adjacent nitrogen atom includes a morpholino group, thiomorpholino group, piperidino group, 1-piperazinyl group, and 1-pyrrolidinyl group.
The type and number of the substituent of the substituted alkyl group are not particularly limited. Preferably, the number of the substituent is from 1 to 3, and examples include a hydroxyl group, a halogen atom (xe2x80x9ca halogen atomxe2x80x9d used herein may be any of fluorine, chlorine, bromine, and iodine atoms), an amino group, a hydroxyamino group, a mono(lower alkyl)amino group, a mono(lower alkoxy)amino group, an alkanoylamino group, an azide group, a heterocyclic group (examples include those exemplified for the aforementioned heterocyclic group and the nitrogen containing heterocyclic group formed together with the adjacent nitrogen atom), a lower alkanoyloxy group, a heterocyclic carbonyloxy group(i.e., heterocycle-C(xe2x95x90O)xe2x80x94O wherein the heterocyclic moiety has the same meaning as that defined in the aforementioned heterocyclic group and the heterocyclic moiety may be substituted with a halogen atom or a lower alkoxycarbonyl group), and a heterocyclic oxy group such as tetrahydropyranyloxy group.
In the definition of the substituent of the substituted lower alkyl group, a lower alkyl moiety of the mono(lower alkyl)amino group, mono(lower alkoxy)amino group, alkanoylamino group, lower alkanoyloxy group and lower alkoxycarbonyl group has the same meaning as that defined in the aforementioned lower alkyl group.
Examples of the salt of the compounds (I) include acid-addition salts, metal salts, ammonium salts, and organic amine-addition salts. Examples of the acid-addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates and phosphates, and organic acid salts such as acetates, maleates, fumarates and citrates. Examples of the metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline-earth metal salts such as magnesium salts and calcium salts, aluminium salts, and zinc salts. Examples of the ammonium salts include ammonium salts and tetramethylammonium salts, and examples of the organic amine-addition salts include salts with morpholine and piperidine. When a salt of the compound (I) is used as an active ingredient of the medicament of the present invention, a physiologically acceptable salt is preferably used.
Preparations of the compounds (I) will be explained below.
Avermectins B1a and B2a, which are used as starting materials for the avermectin derivatives disclosed in the present invention, are isolated from the culture of Streptomyces avermitilis, and they are known compounds (Japanese Patent Unexamined Publication (KOKAI) Nos. (Hei) 3-74397/1991 and 3-254678/1991, and U.S. Pat. No. 5,206,155 and the like). )
In the present invention, 5-O-tri(lower alkyl)silyl-4xe2x80x3-oxoavermectin B1a (the compounds (IIa)), which are starting materials for the preparation of the compounds (Ia), can be synthesized by using avermectin B1a as a starting material according to the method disclosed in Japanese Patent Examined Publication (KOKOKU) No. (Hei) 6-33273/1994 or a similar method thereto. Specifically, the compounds (IIa) used as the starting material can be obtained by subjecting the hydroxyl group at the 5-position of avermectin B1a to tri(lower alkyl)silylation, and then oxidizing the hydroxyl group at the 4xe2x80x3-position. Examples of oxidations other than the method disclosed in Japanese Patent Examined Publication (KOKOKU) No. (Hei) 6-33273/1994 include oxidation with phenyl dichlorophosphate (PhOPOCl2)/triethylamine (TEA)/dimethylsulfoxide (DMSO) in isopropyl acetate, oxidation with tetrapropylammonium perruthenate (Pr4NRuO4)/4-methylmorpholine N-oxide (NMO) in the presence of Molecular Sieves 4A (MS4A) in methylene chloride, and oxidation with sulfur trioxide/pyridine complex in dimethylsulfoxide (DMSO).
5-O-Tri(lower alkyl)silyl-4xe2x80x3,23-dioxoavermectin B2a (the compounds (IIb)), which are starting materials for the preparation of the compounds (Ib), can be obtained by using avermectin B2a as a starting material according to the method disclosed in Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 3-74397/1991 or a similar method thereto, which method comprises the step of producing 5-O-tri(lower alkyl)silylavermectin B2a and the following oxidation at the 23- and 4xe2x80x3-positions.
In the following preparations, when a defined group is changed under conditions for a method to be applied, or the group is unsuitable for carrying out the method, desired compounds can be obtained by employing introduction and elimination of a protective group conventionally used in synthetic organic chemistry [see, for example, Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons Inc. (1981)].
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, R1 is a lower alkoxycarbonylmethylidene group optionally substituted with a heterocyclic group, a lower alkenyloxycarbonylmethylidene group, or a cyanomethylidene group, and R2 is a tri(lower alkyl)silyloxy group (the compounds (IIIa) and (IIIb)) can be prepared by the process set out below: 
(In the scheme, R11a represents a lower alkoxycarbonyl group optionally substituted with a heterocyclic group, a lower alkenyloxycarbonyl group, or a cyano group among the definition of R11; R2a represents a tri(lower alkyl)silyloxy group among the definition of R2; and xe2x80x94X1----Y1xe2x80x94 represents xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94.)
The compound (IIIa) or (IIIb) can be obtained by reacting the compound (IIa) or (IIb) with 1 to 10 equivalents of a compound (IV) represented by the formula: (RO)2P(O)CH2R11a wherein R represents a lower alkyl group having the same meaning as that defined above and R11a has the same meaning as that defined above, in the presence of 1 to 10 equivalents of a base in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours.
As the inert solvent, tetrahydrofuran, ether, benzene, toluene, and the like can be used alone or as a mixture thereof. Examples of the base include potassium tert-butoxide, sodium hydride, potassium hydride, lithium hexamethyldisilazane, and lithium diisopropylamide.
The compound (IIIa) wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is a lower alkoxycarbonyl group optionally substituted with a heterocyclic group and R2 is a tri(lower alkyl)silyloxy group can also be obtained using as a starting material the compound (VIIa) wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is a carboxyl group and R2 is a tri(lower alkyl)silyloxy group which is obtained in Preparation 4 explained below.
The reaction can be carried out by reacting the compound (VIIa) with a corresponding lower alcohol optionally substituted with a heterocyclic group or an ester of a corresponding lower alcohol optionally substituted with a heterocyclic group in the presence or absence of a base in an inert solvent at a temperature ranging from 0xc2x0 C. to a boiling point of a solvent used for one minute to 3 days to prepare the desired compounds.
As the inert solvent, lower alcohols such as methanol, ethanol, propanol and tert-butanol, tetrahydrofuran, ether, chloroform, methylene chloride, 1,2-dichloroethane, and the like may be used. The corresponding lower alcohol optionally substituted with a heterocyclic group or the ester of the corresponding lower alcohol optionally substituted with a heterocyclic group, per se, may be used as the inert solvent.
As the base, N-ethyl diisopropylamine, triethylamine, pyridine, 4-dimethylaminopyridine, and the like may be used.
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is a hydroxymethyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (Va)) can be prepared by the process set out below: 
(In the scheme, R11a1 represents a lower alkoxycarbonyl group optionally substituted with a heterocyclic group, or a lower alkenyloxycarbonyl group among the definition of R1a; xe2x80x94X1a----Y1axe2x80x94 represents xe2x80x94CHxe2x95x90CHxe2x80x94, and R2a has the same meaning as that defined above.)
The compound (Va) can be obtained by treating the compound wherein R11a is a lower alkoxycarbonyl group optionally substituted with a heterocyclic group, or a lower alkenyloxycarbonyl group, and xe2x80x94X1----Y1xe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94 (compound (IIIa1) among the compounds obtained in Preparation 1 with an equivalent to an excess amount of a reducing agent in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours.
As the inert solvent, methanol, ethanol, water, tetrahydrofuran, ether, benzene, toluene, pyridine, hexane, methylene chloride, chloroform, 1,2-dichloroethane, and the like may be used alone or as a mixture thereof. Examples of the reducing agent include sodium borohydride, lithium aluminium hydride, and diisobutylaluminium hydride.
The compounds wherein R11 is a halomethyl group can be prepared by treating the compound obtained above wherein R11 is a hydroxymethyl group with a halogenating agent in the presence or absence of a base in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours.
As the inert solvent, methylene chloride, chloroform, 1,2-dichloroethane, benzene, ether, tetrahydrofuran, and the like may be used alone or as a mixture thereof. As the halogenating agent, p-toluenesulfonyl chloride, thionyl chloride, thionyl bromide, and the like may be used. As the base, N-ethyl diisopropylamine, triethylamine, pyridine, 4-dimethylaminopyridine, and the like may be used.
The compounds wherein R11 is an aminomethyl group can also be prepared by reacting the compound wherein R11 is a halomethyl group with an azide-formation agent in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours and carrying out reduction in a conventional manner.
Sodium azide, potassium azide, and the like may be used as the azide-formation agent.
As the inert solvent, ether, tetrahydrofuran, and the like may be used alone or as a mixture thereof.
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is a formyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (VIa)) can be prepared by the process set out below: 
(In the scheme, R2a and xe2x80x94X1a----Y1axe2x80x94 have the same meanings as those defined above.)
The compound (VIa) can be obtained by treating the compound (Va) obtained in Preparation 2 with an equivalent to an excess amount of an oxidizing agent in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours.
As the inert solvent, water, tetrahydrofuran, ether, benzene, hexane, methylene chloride, chloroform, 1,2-dichloroethane, tert-butanol, and the like may be used alone or as a mixture thereof. Examples of the oxidizing agent include pyridinium chlorochromate, pyridinium dichromate, manganese dioxide, and potassium permanganate.
The compound (VIa) wherein the lower alkoxycarbonyl group optionally substituted with a heterocyclic group or the lower alkenyloxycarbonyl group is converted into a formyl group can also be obtained by controlling reaction conditions for reduction of the lower alkoxycarbonyl group optionally substituted with a heterocyclic group or the lower alkenyloxycarbonyl group of the compound (IIIa1) which is used as a starting material in Preparation 2. Examples of the reaction solvent, the reducing agent, equivalents of the reducing agent, the reaction time and the reaction temperature for the reduction of the compound (IIIa1) to obtain the compound (VIa) include those exemplified in Preparation 2.
The compound wherein R11 is a vinyl group or a substituted vinyl group (e.g., R11 is xe2x80x94CHxe2x95x90CHxe2x80x94COOH) can be prepared by subjecting the compound obtained above wherein R11 is a formyl group to the Wittig reaction.
Examples of the solvent, the reaction temperature, equivalents of the reagent, the reaction time and the like for the Wittig reaction are similar to those described in Preparation 1.
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is a carboxyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (VIIa)) can be prepared by the process set out below: 
(In the scheme, R2a and xe2x80x94X1a----Y1axe2x80x94 have the same meanings as those defined above.)
The compound (VIIa) can be obtained by treating the compound (Va) obtained in Preparation 2 with an equivalent to an excess amount of an oxidizing agent in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours. As the inert solvent, water, tetrahydrofuran, ether, benzene, hexane, chloroform, methylene chloride, 1,2-dichloroethane, tert-butanol, and the like may be used alone or as a mixture thereof. Examples of the oxidizing agent include pyridinium dichromate, pyridinium chlorochromate, Jones reagent, chromium trioxide, and potassium permanganate.
The compound (VIIa) can also be obtained by oxidizing the formyl group of the compound (VIa) obtained in Preparation 3 according to the method for preparing the compound (VIIa) from the compound (Va).
The compound (VIIa) can also be obtained by hydrolyzing the compound (IIIa) obtained in Preparation 1 in the presence of an equivalent to an excess amount of an acid or a base in an inert solvent. Examples of the inert solvent include methanol, ethanol, water, tetrahydrofuran, ether, and acetonitrile. Examples of the acid include hydrochloric acid, sulfuric acid, and nitric acid, and examples of the base include sodium hydroxide, potassium hydroxide, and lithium hydroxide.
The compound (VIIa) can also be obtained by treating the compound wherein R11a is a lower alkenyloxycarbonyl group among the compound (IIIa) obtained in Preparation 1 with an equivalent to an excess amount of a reducing agent in the presence of a palladium catalyst in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours. Examples of the inert solvent include methanol and ethanol, and examples of the reducing agent include sodium borohydride, formic acid and hydrazine. Examples of the palladium catalyst include tetrakis(triphenylphosphono)palladium.
The compound wherein R11 is xe2x80x94COxe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94Rx (Rx has the same meaning as that defined above) can be prepared by further reacting the compound obtained above wherein R11 is a carboxyl group with HSxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94Rx (Rx has the same meaning as that defined above).
For the preparation of the compound wherein R11 is xe2x80x94COxe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94Rx (Rx has the same meaning as that defined above) from the compound wherein R11 is a carboxyl group, reaction is generally carried out in the presence of a condensing agent and a base.
Examples of the solvent and the base used in the preparation of the compound wherein R11 is xe2x80x94COxe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94Rx (Rx has the same meaning as that defined above) from the compound wherein R11 is a carboxyl group include the inert solvents and the bases used in the reaction of the compounds (VIIa) and (XV) in Preparation 9 explained below.
As the condensing agent, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate and the like, as well as the condensing agents used in the reaction of the compounds (VIIa) and (XV) in Preparation 9 explained below, may be used.
Examples of the reaction time, the reaction temperature, equivalents of the reagent, and the like for the preparation of the compound wherein R11 is xe2x80x94COxe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94COxe2x80x94Rx (Rx has the same meaning as that defined above) from the compound wherein R11 is a carboxyl group are similar to those used in the reaction of the compounds (VIIa) and (XV) in Preparation 9 explained below.
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is a lower alkanoyloxymethyl group, or a heterocyclic carbonyloxymethyl group: heterocycle-C(xe2x95x90O)xe2x80x94Oxe2x80x94CH2xe2x80x94 wherein the heterocyclic moiety has the same meaning as that defined in the aforementioned heterocyclic group and may be substituted with a halogen atom or a lower alkoxycarbonyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (IXa)) can be obtained by the following method. 
(In the scheme, R7 represents a lower alkyl group or a heterocyclic group which may be substituted with a halogen atom or a lower alkoxycarbonyl group; R2a and xe2x80x94X1a----Y1axe2x80x94 have the same meanings as those defined above. The lower alkyl group, heterocyclic group, halogen atom and lower alkoxycarbonyl group in the definition of R7 have the same meanings as those defined above, respectively.)
The compound (IXa) can be obtained by reacting the compound (Va) obtained in Preparation 2 with an equivalent to an excess amount of the compound (VIIIa) represented by the formula: R7COCl wherein R7 has the same meaning as that defined above, in the presence or absence of an equivalent to an excess amount of a base in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours. Examples of the inert solvent include chloroform, methylene chloride, 1,2-dichloroethane and pyridine, and examples of the base include triethylamine, diisopropylethylamine, pyridine, and dimethylaminopyridine.
The desired compound (IXa) can also be obtained by reacting the compound (Va) with an equivalent to an excess amount of the compound (VIIIb) represented by the formula: (R7CO)2O wherein R7 has the same meaning as that defined above, in the presence or absence of an equivalent to an excess amount of a base in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours. Examples of the inert solvent and the base used include those used in the reaction of the compounds (Va) and (VIIIa).
The desired compound (IXa) can alternatively be obtained by reacting the compound (Va) with an equivalent to an excess amount of the compound (VIIIc) represented by the formula: R7COOH wherein R7 has the same meaning as that defined above, for 1 minute to 24 hours in the presence or absence of an equivalent to an excess amount of a base and in the presence of an equivalent to an excess amount of a condensing agent in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used. Examples of the inert solvent and the base used include those used in the reaction of the compounds (Va) and (VIIIa). Examples of the condensing agent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI) hydrochloride and 1,3-dicyclocarbodiimide.
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is xe2x80x94CHxe2x95x90Nxe2x80x94OR3 wherein R3 has the same meaning as that defined above, or xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94CONH2, and R2 is a tri(lower alkyl)silyloxy group (the compound (XIa)) can be obtained by using the compound (VIa) obtained in Preparation 3 as a starting material by the following method. 
(In the scheme, R9 represents OR3 wherein R3 has the same meaning as that defined above, or NHxe2x80x94CONH2, and R2a and xe2x80x94X1a----Y1axe2x80x94 have the same meanings as those defined above.)
The compound (XIa) can be obtained by reacting the compound (VIa) with an equivalent to an excess amount of the compound (X) represented by the formula: H2Nxe2x80x94OR3 wherein R3 has the same meaning as that defined above or a salt thereof (examples thereof include acid addition salts having the same meaning as that defined above), or an equivalent to an excess amount of a semicarbazide or a salt thereof (examples thereof include acid addition salts having the same meaning as that defined above) for 1 minute to 24 hours in the presence or absence of an equivalent to an excess amount of a base in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used. Examples of the inert solvent include methanol and ethanol. Examples of the base include pyridine, triethylamine, and dimethylaminopyridine.
The compound wherein R11 is xe2x80x94CH2xe2x80x94NHxe2x80x94OR3 can be prepared by reducing the compound obtained above wherein R11 is xe2x80x94CHxe2x95x90Nxe2x80x94OR3. The reduction can be carried out, for example, using a reducing reagent such as diisobutylaluminium hydride in an inert solvent such as dichloromethane, chloroform and tetrahydrofuran.
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is a tetrahydropyranyloxymethyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (XIIa)) can be obtained by using the compound (Va) obtained in Preparation 2 by the following method. 
(In the scheme, R2a and xe2x80x94X1a----Y1axe2x80x94 have the same meanings as those defined above.)
The compound (XIIa) can be obtained by reacting the compound (Va) obtained in Preparation 2 with an equivalent to an excess amount of dihydropyran in the presence of an acid catalyst in an inert solvent. Examples of the acid catalyst include hydrochloric acid, p-toluenesulfonic acid, and pyridinium p-toluenesulfonate. Examples of the inert solvent include chloroform and methylene chloride.
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is an aminomethyl group or a methylaminomethyl group, and R2 is a tri(lower alkyl)silyloxy group (the compound (XIIIa)) can be prepared by using the compound (VIa) obtained in Preparation 3 as a starting material by the following method. 
(In the scheme, R10 represents a hydrogen atom or a methyl group, and R2a and xe2x80x94X1a----Y1axe2x80x94 have the same meanings as those defined above.)
The compound (XIIIa) wherein R10 is a hydrogen atom can be obtained by reacting the compound (VIa) with an equivalent to an excess amount of hexamethyldisilazane in the presence of a catalytic amount to an excess amount of a metal salt in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used for 1 minute to 24 hours, and then adding an equivalent to an excess amount of a reducing agent.
Examples of the inert solvent include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, methanol and ethanol. Examples of the metal salt include zinc chloride, and examples of the reducing agent include sodium borohydride, formic acid, hydrogen gas, and lithium aluminium hydride.
In Preparation 8 explained above, the compound (XIIIa) wherein R10 is a methyl group can be obtained by using heptamethyldisilazane instead of hexamethyldisilazane.
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94, R11 is CONR5R6 wherein R5 and R6 have the same meanings as those defined above, and R2 is a tri(lower alkyl)silyloxy group (the compound (XIVa)) can be prepared by using the compound (VIIa) obtained in Preparation 4 as a starting material by the method set out below. 
(In the scheme, R31 represents NR5R6 wherein R5 and R6 have the same meanings as those defined above, respectively, and R2a and xe2x80x94X1a----Y1axe2x80x94 have the same meanings as those defined above.)
The compound (XIVa) can be obtained by reacting the compound (VIIa) with an equivalent to an excess amount of the compound (XV) represented by the formula: R31H wherein R31 has the same meaning as that defined above, for 1 minute to 24 hours in the presence of a base and a condensing agent in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used.
Examples of the inert solvent include chloroform, methylene chloride, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, methanol, and ethanol. Examples of the condensing agent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI) hydrochloride, and 1,3-dicyclohexylcarbodiimide. Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine, and pyridine.
The compound (XIVa) can also be obtained by treating the compound (VIIa) with a chlorinating agent in an inert solvent or in the absence of a solvent at a temperature ranging from an ice-cooling temperature to a boiling point of a solvent used (at a boiling temperature of the chlorinating agent when no solvent is used) to convert the compound into a corresponding acid chloride, and reacting the resulting acid chloride with the compound (XV) represented by the formula: R31H wherein R31 has the same meaning as that defined above in an inert solvent in the presence of a base at a temperature ranging from an ice-cooling temperature to a boiling point of a solvent used. Examples of the chlorinating agent include phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, and thionyl bromide. Examples of the inert solvent for the chlorination include chloroform, methylene chloride, 1,2-dichloroethane, toluene, and benzene. Examples of the inert solvent for the condensation reaction include chloroform, methylene chloride, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, tetrahydrofuran, methanol, and ethanol. Examples of the base include triethylamine, diisopropylethylamine, dimethylaminopyridine, and pyridine.
Among the compounds (I), the compound wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, and R2 is a hydroxyl group (the compounds (XVIa) and (XVIb)) can be obtained by carrying out deprotection at the 5-position of the compounds obtained in Preparations 1 to 9 and other methods. 
(In the scheme, R1, R2a and xe2x80x94X1----Y1xe2x80x94 have the same meanings as those defined above.)
The compound (XVIa) or (XVIb) can be obtained by treating the compound obtained in Preparations 1 to 9 for 1 minute to 24 hours with a catalytic amount to an amount serving as a solvent of a desilylating agent in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used.
As the inert solvent, tetrahydrofuran, ether, benzene, toluene, pyridine, isopropyl acetate, and the like may be used alone or as a mixture thereof. Examples of the desilylating agent include hydrogen fluoride, hydrochloric acid, hydrogen bromide, sulfuric acid, and hydrogen fluoride/pyridine complex.
The tri(lower alkyl)silyloxy group at the 5-position is sometimes converted into a hydroxyl group depending on reaction conditions for conversion of a functional group at the other position.
Among the compounds (I), the compound wherein R2 represents a carbonyl group together with the carbon atom at the 5-position (the compound (Ic)) can be obtained by oxidizing the compound (XVIaa) wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CHxe2x95x90CHxe2x80x94 among the compound (XVIa) obtained in Preparation 10. 
(In the scheme, R1 has the same meaning as that defined above.)
The compound (Ic) can be prepared by treating the compound (XVIaa) with an equivalent to an excess amount of an oxidizing agent in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used. The reaction is generally finished in 1 minute to 2 days.
Examples of the inert solvent include chloroform, methylene chloride, and 1,2-dichloroethane. Examples of the oxidizing agent include manganese dioxide, pyridinium chlorochromate, chromium trioxide, and pyridinium dichromate.
The compound wherein R2 forms a hydroxime group together with the carbon atom at the 5-position can be obtained by further reacting the resulting compound (Ic) with hydroxylamine or a salt thereof (examples of the salt include acid addition salts having the same meaning as that defined above).
The reaction of the compound (Ic) with hydroxylamine or a salt thereof can be carried out in the presence or absence of a base in an inert solvent at a temperature ranging from xe2x88x9278xc2x0 C. to a boiling point of a solvent used. The hydroxylamine or a salt thereof and the base can be used in an equivalent to an excess amount. The reaction is generally finished in 1 minute to 2 days.
Examples of the inert solvent include lower alcohols such as methanol, ethanol and propanol, ethers such as ether and tetrahydrofuran, and halogenated hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane.
Examples of the base include pyridine, 2,6-dimethylpyridine, dimethylaminopyridine, triethylamine, and diisopropylamine.
The compound, wherein the double bond between the 22- and 23-positions are reduced (ivermectin derivatives, the compounds (B1)), can be prepared by the method set out below. 
By using as a starting material an ivermectin derivative (A1), which is a known compound or can be prepared by a method similar to known methods, the corresponding carbonyl compound can be obtained through oxidation at the 4xe2x80x3-position according to a conventional method. The compound (B1) can be obtained by using the resulting compound for a reaction with the compound represented by the formula: (RO)2P(O)CH2R11b1 wherein R has the same meaning as that defined above, and R11b1 represents a cyano group or a lower alkenyloxycarbonyl group in a manner similar to that described in Preparation 1.
For the preparation of the compound wherein R11b1 is a carboxyl group among the compounds (B1), the compound wherein R11b1 is a cyano group or a lower alkenyloxycarbonyl group among the compounds (B1) is used as a starting material and subjected to a reaction in a manner similar to Preparation 4.
The compound wherein R1 is a cyanomethyl group or a carboxymethyl group and xe2x80x94X----Yxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94 can be prepared by catalytically reducing the compound obtained in Preparation 1 wherein R11 is a cyano group or the compound obtained in Preparation 4 wherein R11 is a carboxyl group for 1 minute to 100 hours in the presence of a catalyst such as triphenylphosphinerhodium chloride and a hydrogen source such as hydrogen and ammonium formate in a solvent such as benzene at a temperature ranging from 0xc2x0 C. to a boiling point of a solvent used.
Deprotection of the hydroxyl group at the 5-position in the above compounds can be carried out according to the method described in Preparation 10.
The compound wherein only the hydroxyl group at the 4xe2x80x3-position of the avermectin B2a derivative (the compound (C)) is oxidized into the corresponding carbonyl group (the compound (D)) or that wherein the hydroxyl groups at the 4xe2x80x3- and 23-positions of the compounds (C) are oxidized into the corresponding carbonyl groups, respectively (the compound (E)), can be prepared by treating the compound (C) with an appropriate oxidizing reagent. 
(In the scheme, R2a has the same meaning as that defined above.)
The compound wherein R11 is a cyano group or a carboxyl group can be prepared by treating the compound (D) wherein only the hydroxyl group at the 4xe2x80x3-position is oxidized into the corresponding carbonyl group in a manner similar to that in Preparation 1 or 4.
Deprotection of the hydroxyl group at the 5-position in the above compounds can be carried out according to the method described in Preparation 10.
Among the compounds (I), the compound (F), wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94, and R11c is a cyano group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group, can be prepared using the compound (D) obtained in Preparation 13 as a starting material in a manner similar to that in Preparation 1.
Among the compounds (I), the compound (G), wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CH2xe2x80x94CH(R13a)xe2x80x94 wherein R13a represents a lower alkylcarbonyloxy group which has the same meaning as that defined above, and R11c is a cyano group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group, can be prepared using the compound (F) obtained in Preparation 14 as a starting material in a manner similar to that in Preparation 5 (i.e., lower-alkanoylation of the hydroxyl group).
Among the compounds (I), the compound (H) wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94 wherein R13 has the same meaning as that defined above, and R11c is a carboxyl group can be prepared by hydrolyzing the compound (F) or (G) wherein xe2x80x94X----Yxe2x80x94 is xe2x80x94CH2xe2x80x94CH(R13)xe2x80x94 wherein R13 has the same meaning as that defined above, and R11c is a cyano group, a lower alkoxycarbonyl group or a lower alkenyloxycarbonyl group in a conventional manner.
The aforementioned methods are typical examples of the preparations of the compounds (I), and the preparations of the compounds (I) are not limited to those explained above. It can be easily understood by a person skilled in the art that the compounds of the present invention can be prepared by other methods and the compounds (I) can also be obtained by carrying out the above methods in an appropriate combination or with an appropriate modification or alteration, if necessary.
In addition, the compounds (I) can also be obtained by an appropriate combination of the methods for converting a functional group which are usually used in the field of synthetic organic chemistry. For example, the compound wherein R2 is a methoxy group can be prepared by a conventional methylation of the hydroxyl group of the corresponding compound wherein R2 is a hydroxyl group. Similarly, the compound wherein R2 is a lower alkoxyl group can be prepared by alkylation. For converting functional groups, desired conversions of functional groups can efficiently be made by protecting appropriate functional groups by methods for protection and deprotection conventionally used in the field of synthetic organic chemistry [e.g., see Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons Inc. (1981)], if necessary.
Specific examples of the aforementioned preparation and other preparations are described in Examples, and accordingly, a person skilled in the art can prepare any compounds falling within the compound (I) by referring to the above general explanations and specific explanations in Examples, and by appropriately choosing starting materials, reagents and reaction conditions and adding an appropriate alteration or modification, if necessary.
Purification of the desired compounds in the aforementioned preparations can be made by an appropriate combination of methods ordinarily used in the filed of synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, crystallization, and various chromatography and the like. Synthetic intermediates may be subjected to a next reaction without purification.
Isomers such as regio isomers, geometrical isomers, tautomers and optical isomers may exist as the compounds (I). Any possible isomers and mixtures thereof in any proportion fall within the scope of the present invention. When a bond of a functional group that substitutes on a carbon atom forming a double bond is represented by a waved line in the specification, it means that the compound is an E- or Z-compound, or a mixture thereof.
For the preparation of a salt of the compound (I), a resulting salt, per se, may be purified when the compound (I) is obtained in the form of a salt. When a product is obtained in a free form, a salt may be isolated and purified after dissolving or suspending the product in a suitable solvent, and adding an acid or a base thereto to form a salt. The compounds (I) and salts thereof may exist in the forms of adducts with water or various solvents (i.e., hydrates or solvates), and these adducts also fall into the scope of the present invention. Moreover, any forms of crystal also fall into the scope of the present invention.
Specific examples of the compounds (I) obtained according to the present invention are shown in Tables 1 to 8. However, the compounds of the present invention are not limited to these examples. In the tables, OTBDMS represents tert-butyldimethylsilyloxy (OSi(CH3)2C(CH3)3), and (a) and (b) represent two isomers based on the hydroxyl group of the oxime moiety (Compounds 9 and 10, and Compounds 12 and 13) or two isomers based on the exomethylene at the 4xe2x80x3-position (Compounds 18 and 19). The isomers appended by (a) represent those having a larger Rf value (lower polarity) and the isomers appended by (b) represent those having a smaller Rf value (higher polarity) in thin-layer chromatography. As a developing solvent, one of the following solvents was used.
Toluene/acetone=4/1
Toluene/ethyl acetate=6/1
As the active ingredient of the medicament of the present invention, one or more substances selected from the group consisting of the compounds in the free form and physiologically acceptable salts thereof, and hydrates thereof and solvates thereof can be used. Any mixture of isomers or an isomer in a pure form may be used. The medicament of the present invention is generally provided in the form of a pharmaceutical composition which comprises one or more pharmaceutical additives and the aforementioned substance as an active ingredient. The route of administration is not particularly limited, and the medicament can be orally administered using preparations such as tablets, granules, capsules, syrups and powders, or parenterally administered by means of injection, intrarectal administration, transdermal administration or the like. Pharmaceutical formulations suitable for oral or parenteral administration are well-known to persons skilled in the art, and they can appropriately choose pharmaceutical additives suitable for the manufacture of the pharmaceutical formulations.
The medicament of the present invention may be applied to various parasitic diseases, and the kinds of the parasitic disease are not particularly limited. The medicament of the present invention may be applied to a human or a mammal other than a human. When the medicament is applied to a mammal other than a human, the medicament may be administered as a pharmaceutical composition, or alternatively, a pharmaceutical composition or the aforementioned active ingredient per se may be added to a feed. The compound of the present invention may be applied as pesticides such as an agent for controlling injurious insects such as blowflies, cockroaches, fleas and the like.